This project seeks to study mechanisms by which tumor viruses or cellular genes contribute to oncogenesis and to devise approaches to prevent or reverse such changes in cells. The oncogenecity of p21 ras genes with a single point mutation has not been established for normal cells, although ras genes with single mutations have been found in a variety of human and animal tumors. The ras gene of Harvey murine sarcoma virus (Ha-MuSV), which contains two point mutations (amino acids 12 and 59), is highly oncogenic in vivo. Using recombinants between a normal cellular ras gene and Ha-MuSV ras gene, we have determined that viruses containing either point mutation were oncogenic in vivo. Using Ha-MuSV ras mutants, we have also determined that the carboxy terminus of the p21 protein is required for the transforming activity of the protein, its membrane localization, and its binding of lipid. Papillomavirus research has been both basic and applied. Using frame shift mutants of cloned viral DNA, we have found that bovine papillomavirus (BPV) contains at least two genes which can independently transform established mouse tissue culture cells. We have also studied the clinical response of patients with epidermodysplasia verruciformis, a disease of chronic widespread wart virus infection, to human leukocyte interferon (IFN). Short term treatment with intralesional or systemic IFN resulted in a marked diminution in the size of warts in each of six patients and to a decrease in the number of virus-positive cells in lesional skin.